4-phenalkyl-3-keto-3.4-dihydro-1.4-benzoxazines and process for the manufacture of same



callyvaluable properties.

patented Mar. 20, 1934 4 PHENALKYL 3 KETO-3A-DIHYDRO-L4- BENZOXAZINESAND PROCESS FOR THE MANUFACTURE OF Ernst Preiswerk and SAME HeinrichMayer, Basel,

Switzerland, assigncrs to Hoifmann-La Roche 1110., Nutley, N. 3., acorporation of New Jersey No Drawing. Application January 7, 1932,Serial No. 585,394. In Germany April 17, 1931 6 Claims.

It is known that by the action of alkyl iodide on an alkali salt of3-keto-3.c-dihydro-lA-benzoxazine an alkyl group is introduced in the 4-position. Thus Wheeler and Barnes (American 5 Chemical Journal, vol. 20,page 555) described the methyland ethyl-compound. Other derivatives of3-keto-3.4-dihydro-1Jl-benzoxazine, alkylated in the 4-position, mostparticularly the aralkyl compounds, have not yet been prepared.

It has now been found that by aralkylation oiB-keto-B.4-dihydro-1.4-benzoxazine, its derivatives and products ofsubstitution, their alkali or alkaline earth salts respectively, aralkylcompounds are obtained, which possess therapeuti- Whereas' the i-alkylderivatives only have a very weak analgesic action, the l-aralkylcompounds have proved to be excellent spasmolytics, their toxicity atthe same time being very slight. They are therefore to be used fortherapeutic purposes.

The aralkylation of 3-keto-3A-dihydro-1A- benzoxazine and itsderivatives, their alkali and alkaline-earth salts respectively may bedone in many different ways. It is for instance by no means necessary touse aralkyl iodides. With the aid of the aralkyl bromides and chlorides,which are technically more easily obtained and cheaper, the reaction islikewise very easily carried out and the yield is excellent.

Example 1 149 parts by weight of 3-keto-3.4-dihydro-l. ibenzoxazine arewell mixed with 138 parts by weight of calcined and sieved potassiumcarbonate and heated for 6 hours with 253 parts by weight of benzylchloride in an oil bath at 160 C. while stirring. The reaction productis then left to cool to 106 C. and the excess of benzyl chloride isdistilled off with steam. Hereafter 30 parts by weight of a 30% solutionof sodium hydroxide are added dropwise in order to dissolve any tracesof unchanged 3-keto-3.4 dihydro-1.4- benzoxazine. On being left to cool,the reaction product, which at first is oily and insoluble in water andsodium hydroxide, crystallizes and is then separated from the alkalineliquid. The yield is nearly theoretical. For purification the reactionproduct may be distilled in vacuo and recrystallized from petroleumether and methyl alcohol. The pure4-benzyl-3-keto-3.1-dihydrolA-benzoxazine melts at 70-71" C. The productis represented by the following graphic formula:

O EH:

JH: aHu

Example 2 By dissolving its parts by weight of 3-keto-3,-i-dihydro-l.4-benzoxazine in 2590 parts by volume of a file-normalbaryta solution and evaporating the solution in vacuo, the dry bariumsalt is first obtained. After heating it with 300 parts by weight ofbenzyl-chloride for 8 hours to 100 C. while stirring, the benzylationwill be complete. The excess of benzyl chloride is then blown off withsteam, the reaction product, which on cooling crystallizes, washedseveral times by decantation with Water in order to remove the bariumsalts. For further purification one may proceed in the manner describedin Example 1. The product is represented by the following graphicformula: a

6H5 Example 3 247 parts by weight of dry 2-phenyl-3-keto-3.4-dihydro-l.4-benzoxazine sodium (the 2-phenyl-3-keto-3.4-dihydro-lA-benzoxazine melting at 164 C. may beobtained by reduction of o-nitrophenoxyphenylacetic ester formed byinteraction between dry o-nitrophenol potassium and phenylbromaceticester) are heated under a reflux condenser to the boiling point with 260parts by weight of benzyl bromide and 500 parts by weight of benzenewhile stirring for 4 hours. When the conversion is erminated, thebenzene and excess of benzyl bromide are removed with steam, then 30parts by weight of a 30 solution of sodium hydroxide are added in orderto remove any traces of the unchanged compound, the reaction product isleft to cool and separated from the alkaline liquid. Afterrecrystallization from methyl-alcohol the 2-pheny1-4-benzyl-3-keto-3Aedihydro-lA-benzoxazine is obtained in needles melting at 90 C.The product is represented by the following graphic formula:

holic solution of sodium ethylate prepared from 35 parts by weight ofmetallic sodium and 700 parts by weight of alcohol. Then 200 parts byweight of benzyl chloride are added and the solution boiled under areflux condenser. After about 3 hours the conversion is terminated, afact noticeable by the attainment of neutrality to phenolphthalein.After addition of 60 parts by weight of a 30% solution of sodiumhydroxide and distillation with steam, the reaction product is treatedin the manner described in Example 1. Thea-benzyl-5-methyl3-keto-3.4-dihydro-1.4 benzoxazine is obtained incolourless needles melting at 118 C. The product is represented by thefollowing graphic formula:

O CH; N

The substituted benzoxazine used as starting material may be obtained inquite analogous manner to the unsubstituted compound. Its melting pointis 205 C.

Example 5 149 parts by weight of 3-keto-3A-dihydro-1.4- benzoxazine aredissolved in 1000 parts by volume of a normal methyl alcoholic solutionof benzylphenyldimethylarnmoniumhydroxide and the solution heated undera reflux condenser to the boiling point. After a short time the alkalinereaction of the solution to phenolphthalein will have disappeared. Ifthe reaction product is then treated in the manner already describedseveral times, the 4-benzyl-3-keto-3.4-dihydrolA-benzoxazine is obtainedin excellent yield. The product is represented by the following graphicformula:

(3H2 (J uHS Example 6 184 parts by weight of the dry potassium salt of3-'keto-3.4dihydro-1.4-benzoxazine are heated with 240 parts by weightof o-chlorobenzylchloride in a boiling water bath, until the productshows no reaction to moist phenolphthalein paper, which will be afterabout 2 hours. After removing the excess of o-chlorobenzylchloride withsteam, adding to the residue 60 parts by weight of a 30% solution ofsodium hydroxide and letting the product cool while stirring, thel-o-c'hlorobenzyl-3-keto-3. l-dihydro-1.4 benzoxazine, which afterrecrystallization from methyl alcohol melts at 105 0., is obtained. Theproduct is represented by the following graphic formula:

Example 7 149 parts by weight of 3-keto-3.4-dil1ydro-l.4- benzoxazineare stirred together with 150 parts by weight of water and 12'- parts byweight of benzyl chloride. The mixture is heated to 8G9G C. Then 140parts by weight of a 30% solution of sodium hydroxide are added andafter 4 hours a further 70 parts by weight, the product being allowed tocool while stirring. The compound thus obtained is identical with thecompound described in Example 1. From the alkaline solution separatedfrom the reaction product unchanged 3-keto-3.4-dihydro-1.4-benzoxazinemay be obtained by acidification. The product is represented by thefollowing graphic formula:

Example 8 171 parts by weight of the dry sodium salt of3-keto-3A-dihydro-1A-benzoxazine and 230 parts by weight offl-phenylethylbromide are stirred for several hours at 100 C., until asample of the product does not react to moist phenolphthalein f paper.The reaction .product is then treated as described in Example 1 andl-(p-phenylethyl) -3- keto-3.4-dihydro-1.4-benzoxazine is obtained inneedles melting at 87 C. The product is represented by the followinggraphic formula:

1. A 4-phenalkyl-3-keto-3.4-dihydro-1.4-benzoxazine having thestructural formula:

consists in heating a phenyl-alkyl-halide with a compound of thefollowing general formula:

\Hz to sists in heating benzyl chloride with an alkaliforming metal saltof 3-keto-3.4-dihydro-1.4-

, benzoxazine.

6. A process for the manufacture of -benzyl-3-keto-3.4-dihydro-1.-benzoxazine which consists in heating benzylchloride with the barium salt of 3-ket0-3.4-dihydro-l.-benzoxazine.

ERNST PREISWERK. HEINRICH MAYER.

